The TBX5 transcription factor plays a critical role in establishment of cardiac structure, and TBX5 mutations cause human congenital heart disease. We have demonstrated that Tbx5 plays a critical role in chick proepicardial cell migration during embryonic establishment of the epicardium and coronary vasculature. In human embryonic tissue, TBX5 expression is high in the epicardium and coronary vascular wall but is inactivated in the subepicardial cells delaminating from the epicardium to form coronary vessels. Preliminary data also suggest that Tbx5 activity in the proepicardium upregulates expression of the Ets-2, a transcription factor that has also been implicated in coronary vasculogenesis. We then hypothesize that Tbx5-dependent transcriptional circuits involving Ets-2 play critical roles in proepicardial, epicardial and coronary vessel development during embryogenesis. Furthermore, because we have shown that Tbx5 activities is re-expressed in adult human and murine bone-marrow derived stem cells differentiating into angioblasts, we hypothesize that Tbx5 can modify adult endothelial precursor cell differentiation, potentially via Ets-2 activation, and may thereby participate in cell mediated revascularization of the adult ischemic heart. In this application, we propose to utilize chick and mouse experimental models: (1) To determine the contributions of Tbx5 to establishment of the eppicardium and coronary vessels; (2) To define the impact of Tbx5 on Ets-2 expression in the proepicardial derivatives and the contribution of Ets-2 to Tbx5 signaling during epicardial development and coronary vasculogenesis; (3) To determine the role of Tbx5 expression during angioblastic differentiation of adult mammalian bone marrow derived stem cells. These studies will highlight critical transcriptional regulators of coronary vascular progenitor cell behavior and will both shed light on fundamental mechanisms that underlie the development of the coronary vasculature as well as foster novel targets to promote the revascularization of cardiac tissue in individuals with ischemic cardiomyopathies.